Endothelial to Mesenchymal Transformation Mechanobiology

发育中的心脏瓣膜、纤维化心脏组织的生成和钙化主动脉瓣结节的形成都共享一个共同的成分-激活的成纤维细胞。成纤维细胞活化的一个来源是内皮细胞向间充质细胞的转化(EndMT)，即成熟内皮细胞向间充质细胞分化。EndMT首先在胚胎心脏瓣膜发育中被观察到，但最近的研究表明，间质转化也可以发生在伤口愈合、癌症、心脏纤维化和钙化性主动脉瓣疾病中。EndMT在成人应用中的机制和功能作用，特别是在对组织力学的反应中，尚未得到充分的研究。该奖项支持机械生物学在主动脉瓣EndMT中的作用的基础研究。确定导致EndMT的细胞和组织水平的条件，以及间充质转化的细胞如何促进疾病，将有助于了解主动脉瓣如何钙化并填补心血管医学中未得到满足的需求。更广泛地说，这项工作将为理解纤维性疾病、癌症转移和生物材料设计提供更好的方法。这项研究需要几个领域的专业知识，包括组织工程、生物力学和计算生物学；这一多学科的方法将被整合起来，以促进研究生、本科生和K-12科学和工程教育。EndMT已在钙化结节附近的人类瓣膜中观察到，主动脉瓣疾病中存在的因素，包括炎症细胞因子、病理循环应变和剪应力变化，已分别被证明可诱导成人主动脉瓣内皮细胞的细胞转化。初步工作还表明，模拟瓣膜病变条件的细胞外基质成分强烈刺激间充质转化和钙化。到目前为止，还没有研究将EndMT的程度与瓣膜钙化联系起来。研究小组将设计新的细胞培养模型和随机/连续混合计算模型，以测试EndMT产生的激活的成纤维细胞促进瓣膜基质重塑、炎症细胞因子释放和钙化结节形成的假设。研究目的是确定细胞外基质-主动脉瓣内皮细胞相互作用对EndMT的影响，确定间充质转化细胞是否促进钙化，并使用混合计算模型预测间充质转化细胞的进化和生长。这项研究计划的长期目标是开发能够(1)确定促进或抑制EndMT及其后续影响的因素，以及(2)提供一个研究治疗干预措施的平台，这可能对科学家可用的技术产生重大影响，并导致人类疾病的新疗法。

A developing heart valve, the generation of fibrotic heart tissue, and the formation of calcified aortic valve nodules all share a common component - activated fibroblasts. One source of activated fibroblasts is endothelial to mesenchymal transformation (EndMT), which is the differentiation of mature endothelial cells into mesenchymal cells. EndMT was first observed in embryonic heart valve development, but recent studies have shown that mesenchymal transformation can also occur in wound healing, cancer, cardiac fibrosis, and calcific aortic valve disease. The mechanisms and functional role of EndMT in adult applications, especially in response to tissue mechanics, have not been fully investigated. This award supports fundamental research on the role of mechanobiology on EndMT in aortic heart valves. Determining the cellular and tissue-level conditions that lead to EndMT, and how mesenchymally transformed cells promote disease, will provide an understanding of how aortic valves calcify and fill an unmet need in cardiovascular medicine. More broadly, this work will provide better methods for understanding fibrotic disease, cancer metastasis, and biomaterial design. This research requires expertise from several fields including tissue engineering, biomechanics, and computational biology; and this multidisciplinary approach will be integrated to promote graduate, undergraduate, and K-12 science and engineering education.EndMT has been observed in human valves near calcified nodules, and factors present in aortic valve disease including inflammatory cytokines, pathological cyclic strain, and altered shear stress have individually been shown to induce cell transformation in adult aortic valve endothelial cells. Preliminary work has also shown that extracellular matrix composition mimicking diseased valve conditions strongly stimulates mesenchymal transformation and calcification. No studies to date have linked the degree of EndMT to valve calcification. The research team will engineer novel cell culture models and hybrid stochastic/continuum computational models to test the hypothesis that the activated fibroblasts generated from EndMT promote valve matrix remodeling, inflammatory cytokine release, and calcified nodule formation. The research objectives are to characterize the extracellular matrix-aortic valve endothelial cell interactions that impact EndMT and determine if mesenchymally transformed cells promote calcification, and to predict mesenchymally transformed cell evolution and growth using hybrid computational models. The long-term goal of this research program is to develop tools that can (1) determine the factors that promote or inhibit EndMT and its subsequent effects and (2) provide a platform for investigating therapeutic interventions, which could have a major impact on the technology available to scientists and lead to novel treatments for human disease.